Paramyxoviruses have a natural tropism for the respiratory tract and induce a high level of local and systemic immunity. A number of these viruses do not spread significantly beyond the respiratory tract, which would be a safety factor. Live attenuated versions of a number of paramyxoviruses, such as the human parainfluenza viruses (HPIVs), are being developed as vaccines against their respective diseases. These also represent potential vectors can be used to rapidly develop recombinant vaccines against newly identified pathogens. Previously, we evaluated this strategy using an existing live-attenuated vaccine virus, BHPIV3, that is being developed as an intranasal pediatric vaccine against HPIV3. We used BHPIV3 as a vector to express the structural proteins of the Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV) individually and in combinations. Using the hamster model, we showed that the spike S glycoprotein is the only significant neutralization and protective antigen among the SARS structural proteins. We also showed that the BHPIV3-S recombinant was immunogenic and protective as an intranasal vaccine against SARS-CoV in African green monkeys, an animal model that is anatomically and phylogenetically more closely related to humans. This validated the strategy of intranasal immunization against a highly pathogenic agent. As currently constructed, the BHPIV3-S virus is an excellent candidate for clinical evaluation in infants and young children as vaccine that likely would be highly-attenuated, safe and immunogenic against both HPIV3 and SARS. However, it is unlikely that any replicating viral vector bearing the protective antigens of a common human pathogen such as HPIV3 would replicate sufficiently well in adults to be satisfactory immunogenic due to prevalence of neutralizing antibodies to these pathogens resulting from natural exposure. To address this problem, we have examined Newcastle disease virus (NDV) as a vector. NDV is an avian pathogen that is antigenically distinct from the HPIVs, and there is not extensive natural immunity in humans. Seroconversion is common in bird handlers, suggesting that NDV can cause inapparent infection in humans. NDV exists naturally in a variety of strains that exhibit a wide spectrum of virulence in birds, ranging from highly virulent (velogenic), to moderate virulence (mesogenic), to low virulence (lentigenic). Two strains were evaluated: the attenuated vaccine strain LaSota (NDV-LS) that replicates mostly in the chicken respiratory tract and the Beaudette C (NDV-BC) strain of intermediate virulence that produces mild systemic infection in chickens. A recombinant version of each virus was modified by the insertion, between the P and M genes, of a gene cassette encoding the HPIV3 hemagglutinin-neuraminidase (HN) protein, a test antigen with considerable historic data. The recombinant viruses were administered to African green monkeys (NDV-BC and NDV-LC) and rhesus monkeys (NDV-BC only) by the combined intranasal and intratracheal routes at a dose of 10(6.3) PFU per site, with a second equivalent dose administered 28 days later. Little or no virus shedding was detected in nasal/throat swabs or tracheal lavages following either immunization with either strain. In a separate experiment, direct examination of lung tissue confirmed a highly attenuated, restricted pattern of replication by parental NDV-BC. The serum antibody response to the foreign HN protein induced by the first immunization with either NDV vector was somewhat less than that observed following a wild type HPIV3 infection, whereas the titer following the second dose exceeded that observed with HPIV3 infection even though HPIV3 replicates much more efficiently than NDV in these animals. NDV appears to be a promising vector for the development of vaccines for humans to control localized outbreaks of emerging pathogens.